Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1. J Cell Physiol 2009 Jan;218(1):94-103
Date
08/30/2008Pubmed ID
18726995Pubmed Central ID
PMC2597846DOI
10.1002/jcp.21570Scopus ID
2-s2.0-58649096802 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
Thrombospondin-1 (TSP-1) treatment of dermal microvascular endothelial cells (MvEC) has been shown to upregulate Fas ligand (FasL) and to induce apoptosis by a mechanism that requires caspase-8 activity. We have examined the potential anti-angiogenic effects of TSP-1 on primary human brain MvEC. The addition of TSP-1 to primary human brain MvEC cultured as monolayers on type 1 collagen, induced cell death and apoptosis (evidenced by caspase-3 cleavage) in a dose- (5-30 nM) and time-dependent (maximal at 17 h) manner. TSP-1 treatment for 17 h induced caspase-3 cleavage that required caspase-8 activity and the tumor necrosis factor receptor 1 (TNF-R1). We did not find a requirement for Fas, or the tumor necrosis-related apoptosis-inducing ligand receptors (TRAIL-R) 1 and 2. We confirmed the findings using caspase inhibitors, blocking antibodies and small interfering RNA (siRNA). Further analysis indicated that the TSP-1 induction of caspase-3 cleavage of primary human brain MvEC adherent to collagen required the synthesis of new message and protein, and that TSP-1 induced the expression of TNFalpha mRNA and protein. Consistent with these findings, when the primary human brain MvEC were propagated on collagen gels mAb anti-TNF-R1 reversed the inhibitory effect, in part, of TSP-1 on tube formation and branching. These data identify a novel mechanism whereby TSP-1 can inhibit angiogenesis-through induction of apoptosis in a process mediated by TNF-R1.
Author List
Rege TA, Stewart J Jr, Dranka B, Benveniste EN, Silverstein RL, Gladson CLAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ApoptosisBase Sequence
Brain
CD36 Antigens
Caspase 3
Cells, Cultured
Endothelial Cells
Humans
Microcirculation
Neovascularization, Physiologic
RNA, Messenger
RNA, Small Interfering
Receptors, Tumor Necrosis Factor, Type I
Thrombospondin 1
Tumor Necrosis Factor-alpha